At present, the polyethylene glycol derivatives are widely used in combination with proteins, peptides, and other therapeutic agents to extend the physiological half-life of drugs referred to, reduce immunogenicity and toxicity. In clinical use, PEG and its derivatives which act as the carrier in the production of pharmaceutical preparations have been widely used in lots of medicines. The attempts to bond PEG to the drug molecules have also seen significantly development in the past decade, and widely used in many approved medicines such as PEGASYS® (peginterferon alfa-2a, which is a combination of α-interferon and polyethylene glycol with a longer circulation half-life and a better therapeutic effect. Metabolic processes of polyethylene glycol in the human body have been quite clear, which is a safe synthetic polymer material without side effects.
In terms of drug modification, the latest research direction is to connect a targeted molecule to the drug molecules through polyethylene glycol to enrich drug molecules near the focus, so as to achieve the best therapeutic effect. For example, anticancer medicine is connected to monoclonal antibodies. According to the recent research of our company, the combination of two different medicinal molecules through polyethylene glycol can maintain the aforementioned increase of physiological half-life and reduce immunogenicity and toxicity, while giving full play to the two molecules' synergies. Intermolecular synergy is very important in the Chinese medicine theory. When two or more different molecules are connected with polyethylene glycol, a PEG derivative with metachronous double functional groups is needed. Currently, our company could be able to produce a variety of PEG derivatives with metachronous double functional groups, such as MAL-PEG-NHS, acrylic acid-PEG-NHS, and HO-PEG-COOH. However, those PEG derivatives with metachronous double functional groups are straight-chain polyethylene glycol derivatives.
Straight-chain polyethylene glycol derivatives with metachronous double functional groups are limited to some extent in applications. The ratio of two molecules connected by the straight-chain ethylene glycol derivatives with metachronous double functional groups is basically 1:1. If one molecule is needed more than another one, for example, if one molecule has with low in vivo activity, more connections will be required for the low activity molecules than the high-activity molecules, which is a challenge to the straight-chain polyethylene glycol derivatives with metachronous double functional groups. At the same time, in terms of drug carrying, multi-arm polyethylene glycol is advantageous over the straight-chain polyethylene glycol. Straight-chain polyethylene glycol derivatives with metachronous double functional groups can only carry two molecules, while the multi-arm polyethylene glycol has several end groups, and thus has more than one drug connection points, and can carry several drug molecules. At present, multi-arm polyethylene glycol is widely used in the PEG-modification of peptides and small molecule drugs. However, the multi-arm PEG derivatives on the market only have the same active groups such as 4-arm polyethylene glycol succinate —NHS ester, (4arm-SS). The U.S. Pat. No. 6,046,305 shows a star-shaped polyethylene glycol derivative formed through polymerization reaction with only one active group. At the same time, one arm of this star-shaped polyethylene glycol derivative is connected with the other arms through the non-ether bond, such as the amide bond or ester bond. This connection is different in the way, and can reduce the stability of the derivatives.